Strategies for combating tuberculosis (TB), including new therapeutics and vaccines, depend on a better understanding of the mechanisms by which Mycobacterium tuberculosis (Mtb) evades host defenses and modulates immune responses to its benefit. A major knowledge gap in the TB field is our lack of insights into why Mtb-specific T cell responses are poorly protective against TB and how we can improve these responses. While IFN-? and T-helper 1 (Th1) cells are necessary for controlling Mtb infection, they are not sufficient for protection against TB disease. Recently, Th17 cells have emerged as important for protective immunity to TB, but the mechanisms that lead to the generation of Th17 subsets remain unclear. Dendritic cells (DCs) are crucial for activating and shaping antigen-specific T cell differentiation through cytokine production, costimulatory functions and antigen presentation but the molecular mechanisms used by Mtb to manipulate DC functions and shape differentiation of Th subsets are poorly understood. The focus of this application is to investigat mechanisms used by Mtb to modulate DC functions, to examine how Mtb-DC interactions impact generation of Mtb-specific Th1 and Th17 cell immunity and to use these insights to design more efficacious TB vaccines. We build on insights gained from studying the molecular and biochemical functions of an Mtb serine protease, Hip1. We identified a novel immune evasion mechanism mediated by Hip1 that dampens TLR2- dependent innate responses through proteolysis of a target substrate, GroEL2 and impairs CD40-dependent costimulatory capacity of DCs. We hypothesize that Hip1-mediated immunomodulation of DCs promotes sub- optimal antigen-specific T cell responses, impedes generation of Mtb-specific Th17 responses and thereby compromises protective immunity to TB. We will combine mycobacterial genetics, immunology and mouse models to investigate the molecular basis for GroEL2 modulation of TLR2 pathways, Th17 responses and its role in promoting pathogenesis in vivo (Aim 1). Second, we will investigate how CD40-dependent costimulation shapes DC-T cell crosstalk in TB and test the hypothesis that boosting CD40 engagement will augment Th17 responses and protective immunity (Aim 2). Finally, we will test the hypothesis that deleting hip1 in BCG will improve efficacy of the BCG vaccine in mice (Aim 3). These studies will provide crucial insights into the how Mtb modulates the innate-adaptive immune axis and inform designing efficacious vaccines for TB.